5-(2-methylenealkanoyl)-benzofuran 7-carboxylic acids

ABSTRACT

THE PRODUCTION OF 5-(2-METHYLENE-ALKANOYL)-BENZOFURAN-, 5-(2-METHYLENE-ALKANOYL)-INDOLE- AND 5-(2-METHYLENE-ALKANOYL)-BENZOL(B)THIOPHENE-2-CARBOXYLIC ACIDS BY REACTION OF THE CORRESPONDING 5-(2-DIMETHYLAMINOMETHYLALKANOYL)-DERIVATIVES WITH SODIUM ACETATE IN GLACIAL ACETIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS WITH BASES, A METHOD OF PRODUCING A DIURETIC AND SALURETIC EFFECT IN MAMMALS COMPRISING ADMINISTERING SAID COMPOUNDS TO SAID MAMMALS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAID COMPOUNDS ARE DESCRIBED. A TYPICAL EMBODIMENT IS 5-(2-METHYLENE-BUTYRYL)-6-METHYL-BENZOFURAN-2-CARBOXYLIC ACID.

3,580,931 -(2-METHYLENEALKANOYL)-BENZOFURAN Z-CARBOXYLIC ACIDS JanosZergenyi, Riehen, and Ernst Habicht, Oberwil, Switzerland, assignors toGeigy Chemical Corporation,

Ardsley, N.Y.

No Drawing. Filed July 22, 1968, Ser. No. 746,262 Claims priority,application Switzerland, July 28, 1967, 10,764; Sept. 29, 1967, 13,637Int. Cl. C07d 5/42 US. Cl. 260346.2 Claims ABSTRACT OF THE DISCLOSUREDETAILED DESCRIPTION The present invention pertains to heterocycliccarboxylic acids, processes for the production thereof, a method ofproducing a diuretic and saluretic efiect as well as pharmaceuticalcompositions.

More particular, the present invention pertains to heterocycliccarboxylic acids of the Formula I R-i J-oo I Y wherein R is hydrogen orlower alkyl; X is oxygen, sulfur, the imino or the methylimino group, Yis hydrogen, methyl, fluoro, chloro or bromo, and each of Z and Z takenindividually is hydrogen, lower alkyl, lower alkoxy, fluoro, chloro orbromo;

as well as to the pharmaceutically acceptable salts thereof with a base.

These compounds have been found to possess valuable pharmacologicalproperties. In particular, they have a diuretic and saluretic activity.These properties characterise the compounds of the invention suitablefor the treatment of disturbances which are due to insufficientexcretion of urine and of electrolytes, especially of sodium chloride.Such disturbances are the cause of oedema and hypertension. The newsubstances administered orally in low doses increase the excretion ofurine and of sodium and chlorine ions to a considerable extent.

In the heterocyclic carboxylic acids of Formula I, Z occupies the 4- or6-position and Z the 6- or 7-position of the heterocyclic ring. By theterm lower alkyl and the derivation thereof using the root alk, namelyalkoxy, is intended a group comprising a straight or branchedhydrocarbon chain of from 1 to 4 carbon atoms. Representative of loweralkyl groups are thus, e.g. the methylethyl, propyl, isopropyl, butyl ortert. butyl group. Embraced by the term lower alkoxy are such groups asthe methoxy, ethoxy, propoxy, isopropoxy, butoxy or the'sec. butoxygroup.

United States Patent Ofice 3,580,931 PatentedrMay 25, 1971 Compounds ofFormula I are produced according to a first process by decomposing acompound of Formula II Gilt-Am Z 1 cooH Z2 t 2 wherein R, X, Y, Z, and Zhave the meanings given in Formula I, and Am is the radical of asecondary amine, said secondary amine of Formula III wherein Am is split011. If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

As radical of a secondary amine, Am can be, e.g. the dimethylamino,diethylamino, l-pyrrolidino, l-piperidino, l-hexahydro-lH-azepino or themorpholino group.

A compound of Formula II is preferably decomposed by heating in thepresence of a weak base in a solvent containing hydroxyl groups.Examples of weak bases are sodium acetate or sodium hydrogen carbonate.Examples of solvents containing hydroxyl groups are glacial acetic acidand water.

Compounds of Formula II are produced, for example, as follows:Carboxylic acids of Formula IV, which are also starting materials forthe second process according to the invention, are condensed accordingto Friedel-Crafts in the presence of aluminum chloride in nitrobenzenewith carboxylic acid chlorides of Formula IVa RCH COCl (IVa) wherein Rhas the meaning given in Formula I, to form the corresponding S-alkanoylderivatives. Such S-alkanoyl derivatives are, e.g. the S-acetyl,S-propionyl, S-butyryl, 5,-valeryl or 5-isovaleryl derivatives ofbenzofuran-Z-carboxylic acid, of benzo[b]thiophene-Z-carboxylic acid, ofindole-2-carboxylic acid or of l-methyl-indole-Z-carboxylic acids which,optionally are substituted by the radicals Y, Z and/or Z The S-alkanoylderivatives mentioned are then converted into the corresponding Mannichderivatives with the aid of formaldehyde or paraformaldehyde and asecondary organic amine.

Compounds of Formula -I are produced by a second process according tothe invention by reacting, according to Friedel-Crafts, a compound ofFormula IV COOH wherein X, Y, Z and Z have the meanings given in FormulaI, with a carboxylic acid halide of Formula V CH2 0 R 'C E Q (v3 or witha carboxylic acid anhydride of Formula VI 011, R( JC f W wherein R hasthe meaning given in Formula I, and Q is halogen; If desired, thereaction product of Formula I is converted into a pharmaceuticallyacceptable salt with an inorganic or organic base in a conventionalmanner.

As halogen, Q is preferably chlorine or bromine. Suitable catalysts forthe reaction according to Friedel-Crafts are, e.g. aluminum chloride,stannic chloride, zinc chloride, concentrated sulfuric acid, phosphoricacid, polyphosphoric acid or pyrophosphoric acid, containing hydroxylgroups. The acids are used, preferably, when a carboxylic acid anhydrideis the acylating agent. The reaction is preferably performed in asolvent, such as, e.g. aliphatic or cycloaliphatic hydrocarbons such asheptane or cyclohexane, nitrated hydrocarbons such as nitromethane,nitrocyclohexane or nitrobenzene, halogenated hydrocarbons such ascarbon tetrachloride, ethylene chloride, methylene chloride, oro-dichlorobenzene, and carbon disulfide.

Compounds of Formula II wherein X, Y, Z and Z have the meanings given inFormula I are described in the literature, e.g. benzofuran-Z-carboxylicacid [cf. R. Fittig et al., Ann. Chem. 216, 162 (1 883)],benzo[b]thiophene- 2-carboxylic acid [of P. Friedl'ainder et al., Chem.Ber. 45, 2087 (1912)], indole-2-carboxylic acid [cf. W. Madelung, Chem.Ber. 45, 3521 (1912)], 4-chloroindole- 2-carboxylic acid (cf. H. N.Rydon et al., J. Chem. Soc. 1955, 3499) and l-methyl-indole-Z-carboxylicacid [cf. E. Fischer et al., Chem. Ber. 16, 2245 (1883)]. Othercompounds of this type can be produced in analogy to the literaturereferences cited.

Compounds of Formula I are produced by a third process according to theinvention by simultaneously saponifying the ester group and splitting01f the secondary organic amine from a compound of Formula VII C Hz-A mwherein R, X, Y, Z and Z have the meanings given in Formula I, Am hasthe meaning given in Formula II and R is a lower alkyl or the benzylgroup. If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

This simultaneous saponification and splitting reaction is preferablyperformed by shortly boiling the compound of Formula VII in an aqueousalkanol in the presence of an alkali or alkaline earth metal hydroxideor carbonate.

Compounds of Formula VII, are produced e.g. by esterifying a compound ofFormula II with a lower alkanol or benzyl alcohol. This esterificationhas to be carried out under mild conditions so that the secondary aminogroup is not split off. The compounds of Formula VII are also producedby acylating according to Friedel-Crafts a lower alkyl or benzyl esterof Formula IV with an acid chloride of Formula IVa. The so obtainedester is then converted into the corresponding Mannich derivative ofFormula VII by reaction with formaldehyde or paraformaldehyde and asecondary amine.

Compounds of Formula I are produced by a fourth process according to theinvention by saponifying in con ventional manner a compound of FormulaVIII (VII) COOR Z 2 (VIII) wherein R, X, Y, Z and Z have the meaningsgiven in Formula I and R has the meaning given in Formula VII. Ifdesired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base inconventional manner.

This saponification is, e.g., carried out in a solvent containinghydroxyl groups in the presence of an alkali or alkaline earth metalhydroxyde or carbonate.

Compounds of Formula VIII are produced by heating a compound of FormulaVII in the presence of a weak base, in a solvent containing hydroxylgroups, in a way as described in the first process of this invention.Sodium acetate and sodium hydrogen carbonate which do not saponify theester function can be used as weak bases. Water or lower fatty acidssuch as glacial acetic acid can be used as solvents.

Compounds of Formula I are produced by a fifth process according to theinvention by splitting olf hydrogen halide from a compound of Formula IXZ2 wherein R, X, Y, Z and Z have the meanings given in Formula I and Qhas the meaning given in Formula V. If desired, the reaction product ofFormula I is converted into a pharmaceutically acceptable salt with aninorganic or organic base in a conventional manner.

As halogen atom Q is preferably chlorine or bromine. The elimination ofhydrogen halide is carried out e.g. by boiling the compound of FormulaIX in an organic base, such as collidine or in dimethyl formamide.Hydrogen halide can also be eliminated by boiling a compound of FormulaIX in an organic solvent such as benzene or toluene in the presence ofsilver acetate or by boiling in dimethyl formamide in the presence oflithium bromide or carbonate.

The compound of Formula IX used as starting materials can be produced inanalogy to the second process of this invention by condensing a compoundof Formula IV, according to Friedel-Crafts, in nitrobenzene in thepresence of aluminum chloride, with a carboxylic acid chloride ofFormula IXa wherein R has the meaning given in Formula I and Q themeaning given in Formula V. The compounds of Formula IX can also beproduced by chlorinating or brominating a compound of Formula IXb (IXb)wherein R, X, Y, Z and Z have the meanings given in Formula I. Theproduction of the compounds of Formula IXb is described in the firstprocess of this invention. The chlorination or bromination is, e.g.carried out by adding the equimolar amount of chlorine or bromine to thestirred solution of the compound of Formula IXb in an appropriatesolvent such as glacial acetic acid, nitrobenzene or a halogenatedhydrocarbon.

Compounds of Formula I are produced by a sixth process according to theinvention by treating a compound of Formula X COOH wherein R, X, Y, Zand Z have the meanings given in Formula I and R represents a loweralkyl group with an alkylating agent of Formula Xa Rr-A (Xa) wherein R:has the meaning given in Formula X and A is the monovalent anion of amineral acid,

to give the ternary sulfonium compound of Formula Xb X COOH Z2 (Xb)wherein and boiling this compound in the presence of a weak base untilthe sulfonium group is split 01f. If desired, the reaction product ofFormula I is converted into a pharmacentically acceptable salt with aninorganic or organic base in a conventional manner.

Alkyl halides and dialkylsulfates can be used as alkylating agents. Theelimination of the ternary sulfonium group is performed under similarconditions as the elimination of the secondary amine as described in thefirst process of this invention, i.e. by heating the compound of FormulaXb in the presence of a weak base such as sodium acetate or sodiumhydrogen carbonate in a solvent containing hydroxyl groups like water orlower fatty acids.

The compounds of Formula X can be produced e.g. by boiling, in abuttered aqueous solution of pH 7-9, a compound of Formula II, or a saltof such a compound with a hydrogenhalide, with an excess of a sodiumlower alkyl sulfide of the Formula Xc Na-S-R (Xc) CHz-SOz-Rg R-(LH-CO--I Y wherein R, X, Y, Z and Z have the meanings given in Formula I and Rhas the meaning given in Formula X,

by boiling this compound in the presence of a weak base in a solventcontaining hydroxyl groups. If desired, the reaction product of FormulaI is converted into a pharmaceutically acceptable salt with an inorganicor organic base in a conventional manner.

Sodium acetate or sodium hydrogen carbonate can be used as weak bases.As solvents are preferably used water or lower fatty acids. Thecompounds of Formula XI can be easily produced by treating a compound ofFormula X in an organic solvent with a per acid or hydrogen peroxide.Per acids suitable for this oxidation are, e.g., performic acidperacetic acid or perbenzoic acid. Lower alcohols, lower ketones orlower fatty acids are convenient solvents for this reaction.

For the formation of pharmaceutically acceptable salts can be usedinorganic or organic bases such as alkali or alkaline earth hydroxides,carbonates or bicarbonates. Suitable are thus, e.g. sodium, potassium,magnesium and calcium hydroxides, carbonates or bicarbonates, as well ascholine and triethanolamine. Such salts are produced e.g. by mixing thecompound of Formula I with the equivalent amount of the desired base ina suitable solvent such as water, mixtures of water with an organicsolvent or in organic solvents alone such as methanol, ethanol orpropanol and isolating the salts formed in a conventional manner.

The compounds of the invention have been found to have valuablepharmacological properties, especially diuretic and saluretic activitiescombined with a very low order of toxicity. These favourable propertiesrender the compounds of Formula I and their pharmaceutically acceptablesalts with inorganic or organic bases suitable for the treatment ofdisturbances which are due to insufficient excretion of urine and ofelectrolytes, particularly of sodium chloride. Such disturbances are thecause of oedema and hypertension.

The diuretic and saluretic efiects of the compounds of the invention areillustratively demonstrated in dogs and rabbits. Thus it can be shown byconventional pharmacological experiments that 5-(2-methylene-butyryl)-6methyl benzofuran 2 carboxylic acid, S-(Z-methylenebutyryl) 4 chloroindole 2 carboxylic acid and 5 (2 methylene butyryl) 4 chlorobenzo[b]thiophene-Z-carboxylic acid administered orally or parenterallyin amounts of 5 mg./kg. to dogs and rabbits increase the excretion ofurine and simultaneously of sodium chloride to a considerable extent,whereby no undesirable side effects are observed.

The new active substances or the pharmaceutically acceptable saltsthereof are preferably administered orally.

The daily dosages vary between 50 and 1000 mg. for mammals. Suitabledosage units such as drages and tablets, preferably contain 25500 ml. ofan active substance according to the invention, i.e. 20 to of a compoundof Formula I. They are produced by combining the active substance, e.g.with solid pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, maize starch or amylopectin,also laminaria powder or citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols, to form tablets or dragecores. The latter are coated, e.g. with concentrated sugar solutionswhich can also contain, e.g. gum arabic, talcum and/or titanium dioxide,or with a lacquer dissolved in easily volatile organic solvents ormixtures of solvents. Dyestuffs can be added to these coatings, e.g. todistinguish between varying dosages of active substance.

The following examples further illustrate the production of the newcompounds of Formula I and of hitherto undescribed intermediate productsas well as the production of pharmaceutical compositions but they are byno means the sole methods of producing same. The temperatures are givenin degrees centigrade.

EXAMPLE 1 (a) 2.3 g. of S-butyryl-benzofuran-Z-carboxylic acid, 0.5 g.of paraformaldehyde and 1.0 g. of dimethylamine hydrochloride areslurried in 20 ml. of dioxan and the whole is refluxed for 5 hours whilestirring. The reaction mixture is cooled and evaporated to dryness invacuo. 30 ml. of glacial acetic acid and 3.0 g. of anhydrous sodiumacetate are added to the crudeS-(Z-dimethylaminomethyl-butyryl)-benzofuran-2-carboxylic acidhydrochloride obtained and the mixture is refluxed for 2 hours. Thesolvent is then evaporated in vacuo, the residue is taken up in 50 ml.of water and the aqueous solution is acidified with concentratedhydrochloric acid to pH 2-3. The hydrochloric acid suspension is stirredfor half an hour. The precipitated crystals are then filtered 01f,washed with water, dried in vacuo at 60 and recrystallised frombenzene/hexane. The 5-(Z-methylene-butyryl)benzofuran-Z- carboxylic acidobtained melts at 128-129".

The S-butyryl-benzofuran-2-carboxylic acid used as starting material isproduced as follows:

(b) 5.0 g. of benzofuran-Z-carboxylic acid [cf. \R. Fittig et al., Ann.Chem. 216-, 162 (1883)] are suspended in 20 ml. of nitrobenzene and thesuspension is cooled to 12.0 g. of pulverised aluminium chloride areadded in portions to this suspension so that the temperature of thereaction mixture does not rise above 10. 4.0 g. of butyryl chloride arethen added all at once. The mixture is then heated to room temperaturewhile stirring. Stirring is continued for 24 hours at this temperatureand then it is poured onto 100 g. of ice in 20 ml. of concentratedhydrochloric acid. The hydrochloric acid suspension is extracted twicewith 100 ml. of acetic acid ethyl ester each time, the acetic acid ethylester solution is washed with 50 ml. of water and extracted twice with50 ml. of concentrated sodium hydrogen carbonate solution each time. ThepH of the sodium hydrogen carbonate solution is adjusted to 3 withconcentrated hydrochloric acid, the mixture is stirred for 30 minutes,the precipitated crude product is filtered oil, the filter residue isdried in vacuo at 60 and recrystallised from benzene.S-butyryl-benzofuran-Z-carboxylic acid is obtained, M.P. 179-181.

EXAMPLE 2 8 g. of 4-chloroindole-2-carboxylic acid (cf. H. N. Rydon etal., J. Chem. Soc. 1955, 3499) are slurried in 40 ml. of nitrobenzene.The slurry is cooled to 0 and 20 g. of pulverised aluminium chloride areadded in portions so that the temperature never exceeds 10". Thesuspension is cooled to 0 and 8 g. of Z-methylene butyryl chloride areadded all at once. The mixture is heated to 25 within 20 minutes,stirred for 45 minutes at this temperature and then poured onto 200 g.of ice and 30 ml. of concentrated hydrochloric acid. The hydrochloricacid suspension is extracted twice with 100 ml. of ether each time. Theether extract is washed with water and extracted twice with 50 ml. ofconcentrated sodium hydrogen carbonate solution each time. The sodiumhydrogen carbonate solution is acidified with concentratedhydrochloricacid to pH 2-3 and the precipitated crude product isextracted with ether. The ether solution is dried over magnesiumsulphate, concentrated and the residue is purified by chromatography onsilica gel using benzene/ether/ glacial acetic acid (900:80z20) aseluent. The 4-chloro-5-(2- methylene-butyryl)indole-2-carboxylic acidobtained melts at 19l-l92.

EXAMPLE 3 (a) Crude 3,4-dichloro (2 dimethylaminomethylbutyryl)-indole 2carboxylic acid hydrochloride is obtained analogously to Example 1(a)starting from 3,4- dichloro-S-butyryl-indole 2 carboxylic acid withparaformaldehyde and dimethylamine hydrochloride. It is converted withsodium acetate and glacial acetic acid into3,4-dichloro-5-(Z-methylene-butyryl)-indole-2 carboxylic acid which,recrystallises from benzene/acetic acid ethyl ester, melts at 210-211.The starting material, 3,4-dichloro-5-butyryl-indole-2-carboxylic acid,is produced as follows:

(b) 29 g. of 4-chloroindole-Z-carboxylic acid (cf. H. N. Rydon et al.,J. Chem. Soc. 1955, 3499) are suspended in 400 ml. of ether. 15 ml. ofsulphuryl chloride are added dropwise to this suspension at refluxtemperature, the addition being made within 20 minutes while stirring.The reaction mixture is stirred for another 3 hours at the sametemperature, then cooled and 100 ml. of water are added dropwise. Theether solution is separated from the aqueous solution, the organic phaseis washed with water and extracted twice with 100 ml. of saturatedsodium hydrogen carbonate solution each time. The sodium hydrogencarbonate solution is acidified with concentrated hydrochloric acid topH 2 and the precipitated free carboxylic acid is filtered off, washedwith water and dried in vacuo at 60. Recrystallisation frombenzene/acetic acid ethyl ester yields pure3,4-dichloro-indole-2-carboxylic acid which melts at 240-241 (c) 11.5 g.of the carboxylic acid obtained according to (b) are suspended in 50 ml.of nitrobenzene. 7.5 g. of butyryl chloride are added to thissuspension, the mixture is cooled to 0 and 25 g. of pulverised aluminiumchloride are added in portions so that the temperature of the reactionmixture does not exceed 10. The whole is then stirred for another 5hours at a reaction temperature of 25. The reaction solution is thenpoured onto 200 g. of ice in 40 ml. of concentrated hydrochloric acid, 70 ml. of benzene are added and the suspension is well stirred. Theprecipitate formed is filtered ofi, dried at 60 in vacuo andrecrystallised from dioxan. The3,4-dichloro-5-butyryl-indole-2-carboxylic acid obtained melts at271-272.

EXAMPLE 4 (a) Crudel-methyl-3,4-dichloro-5-(Z-di-methylaminomethyl-butyryl)-indole-2-carboxylicacid hydrochloride is obtained analogously to Example 1(a) starting fromcrude 1-methyl-3,4-dichloro-5-butyryl-indole-2 carboxylic acid withparaformaldehyde and dimethylamine hydrochloride. The crude product isconverted with glacial acetic acid and sodium acetate into l-methyl 3,4dichloro 5 (2- methylene-butyryl)-indole-2-carboxylic acid. M.P. 163-164 (from benzene).

The starting material,1-methyl-3,4-dichloro-5-butyrylindole-2-carboxylic acid, is produced asfollows:

(b) 29 g. of 4-chloroindole-Z-carboxylic acid (cf. H. N. Rydon et al.,J. Chem. Soc. 1955, 3499) are dissolved by gently heating in 300 ml. ofacetone. '35 ml. of dimethyl sulphate are added to this solution and themixture is added dropwise within 30 minutes while stirring to a lightlyboiling suspension of 45 g. of finely pulverised otassium carbonate inml. of acetone. The whole is stirred under reflux for another 3 hours.The precipitated salts are then removed from the solution by filtrationand the filtrate is concentrated in vacuo. Crude 1-methyl-4-chloroindole-Z-carboxylic acid methyl ester remains, to which are added75 ml. of 4 N sodium hydroxide solution, 75 ml. of water and 50 ml. ofethanol. The mixture is refluxed for 30 minutes, cooled, washed withether and acidified to pH 2 with concentrated hydrochloric acid. Theprecipitated crystals are filtered oif, washed with water and dried invacuo at 70. The crude product is recrystallised from dioxan, whereuponthe 1-methyl-4-chloroindole-2-carboxylic acid melting at 252253 isobtained.

The carboxylic acid obtained is converted with sulphuryl chlorideanalogously to Example 3(b) into 1-methyl-3,4-dichloro-indole-Z-carboxylic acid, M.P. 252- 253 (fromdioxan) which is reacted with butyryl chloride analogously to Example1(b) to form 1-methyl-3,4- dichloro-5-butyryl-indole-2-carboxylic acid(crude product).

EXAMPLE 5 (a) Crude 4 methyl 5 (2dimethylaminomethylbutyryl)-benzofuran-2-carboxylic acid hydrochlorideis obtained analogously to Example 1(a) starting from 4-methyl-5-butyryl-benzofuran-2 carboxylic acid with paraformaldehyde anddimethylamine hydrochloride. The crude product is converted with sodiumacetate in glacial acetic acid into4-methyl-5-(2-methylene-butyryl)-benzofuran-Z-carboxylic acid whichmelts at 159-160 (from benzene/acetic acid ethyl ester).

The starting material, 4-methyl-5-butyryl-benzofuran- 2-carboxylic acid,isproduced as follows:

(b) A suspension of 11 g. of 2-methyl-6-hydroxy-benzaldehyde [cf. 0.Anselmino, Chem. Ber. 50, 395 (1917)] and 11 g. of anhydrous potassiumcarbonate in 40 ml. of methylethyl ketone is stirred, refluxed and,within 15 minutes, 20 g. of bromomalonic acid diethyl ester are addeddropwise. The reaction mixture is then boiled and stirred for another 7hours and then concentrated in vacuo. A solution of 10 g. of potassiumhydroxide in 8 ml. of water and 80 ml. of ethanol is added to theresidue, the reaction mixture is refluxed for 2 hours, cooled, 100 ml.of water are added and the ethanol is evaporated in vacuo. The resultantalkaline-aqueous solution is acidified to pH 2-3 with 20% sulphuricacid. The precipitated crystalline crude product is filtered off, washedwith Water, dried in vacuo at 60 and re-crystallised from benzenewhereupon the pure 4 methyl-benzofuran 2 carboxylic acid melts at189-191.

The carboxylic acid obtained is converted into 4-methyl-5-bntyryl-benzofuran-Z-carboxylic acid, M.P. 165-167 (from benzene) withbutyryl chloride in the presence of aluminium chloride analogously toExample 1(b).

EXAMPLE 6 4 methyl-5-(2-methylene-butyryl)-indole-2-carboxylic acid,M.P. 194195 (from benzene) is obtained analogously to Example 2(a) from4-methyl-indole-Z-carboxylic acid [cf. R. Andrisano et al., CA 52, 6313(1958); Gazz. chim. ital. 87, 949 (1957)] with Z-methylenebutyrylchloride in the presence of aluminium chloride in nitrobenzene.

EXAMPLE 7 (a) 1,4-dimethy1 5 (Z-methylene-butyryl)-indole-2- carboxylicacid, M.P. 180-181 (from acetic acid ethyl ester/benzene) is obtainedanalogously to Example 2(a) from l,4-dimethyl-indole-Z-carboxylic acidand 2-methylene-butyryl chloride in the presence of aluminium chloridein nitrobenzene.

The starting material, 1,4-dimethyl-indole-Z-carboxylic acid, isproduced as follows:

(b) A suspension of 35 g. of potassium carbonate in 100 ml. of acetoneis stirred at reflux temperature. A solution of 17.5 g. of4-methyl-indole-2-carboxylic acid [cf. R. Andrisano et al., Gazz, chim.ital. 87,949 (1957)] and 25 ml. of dimethyl sulphate in 150 ml. ofacetone is added dropwise to this suspension within 20 minutes. Thereaction mixture is refluxed for 14 hours, cooled, the precipitate isfiltered off and washed with acetone. The filtrate is concentrated invacuo. The residue, crude 1,4- dimethyl-indole-Z-carboxylic acid methylester, is refluxed for 30 minutes with 120 ml. of 2 N sodium hydroxidesolution and 60 ml. of ethanol. The solution is then cooled, the pH isadjusted to 2 and the precipitated crude carboxylic acid is filtered01f, washed with water and dried in vacuo at 60, After recrystallisationfrom acetic acid ethyl ester/dioxan, 1,4-dimethyl-indole-2-carboxylicacid, M.P. 236237, is obtained.

EXAMPLE 8 (a) 4.0 g. of 5-butyryl-6-methyl-benzofuran-Z-carboxylic acid,0.82 g. of paraformaldehyde and 1.64 g. of dimethylamino hydrochlorideare refluxed for 5 hours in 40 ml. of dioxane while stirring. Thereaction mixture is then evaporated in vacuo. 5.0 g. of sodium acetateas well as 50 ml. of glacial acetic acid are added to the crude5-(2-dimethylaminomethylbutyryl) 6 methylbenzofuran-Z-carboxylic acidhydrochloride obtained and the mixture is refluxed for 2 hours. Theglacial acetic acid is then evaporated in vacuo, the residue is taken upin 100 ml. of water and the aqueous solution is acidified withconcentrated hydrochloric acid to pH 2-3. The hydrochloric acidsuspension is stirred for 1 hour at 20. The precipitated crystals arethen filtered off under suction, dissolved in acetic acid ethyl ester,the solution is dried with anhydrous magnesium sulphate and evaporatedin vacuo. The residue is recrystallised from a small quantity of aceticacid ethyl ester whereupon5-(2-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid isobtained, M.P. 141142.

The starting compound, '5-butyryl-6-methyl-benzofuran-Z-carboxylic acid,is produced as follows:

(b) 10.0 g. of 6-methyl-benzofuran-Z-carboxylic acid [cf. K. von Auwers,Ann. Chem. 408, 255 (1915)] are suspended in 30 m1. of nitrobenzene.28.0 g. of aluminium chloride are added to the suspension in portionswhile cooling with ice so that a reaction temperature of 10 ismaintained. 9.0 g. of butyryl chloride are then added dropwise within 30minutes at the same temperature. The mixture is then stirred for 24hours at 25", after which it is poured into 300 g. of ice and 50 ml. ofconcentrated hydrochloric acid and the hydrochloric acid suspension isextracted twice with 300 ml. of ether each time. The combined ethersolutions are washed with water and extracted twice with ml. ofsaturated sodium hydrogen carbonate solution each time. The pH of thesodium hydrogen carbonate extract is adjusted to 2-3 with concentratedhydrochloric acid and the suspension formed is stirred for 1 hour atroom temperature. The precipitated crystals are filtered off undersuction, washed with water and dissolved in acetic acid ethyl ester. Theacetic acid ethyl ester solution is dried with anhydrous magnesiumsulphate and concentrated in vacuo. Fractional recrystallisation of theresidue from acetic acid ethyl ester/dioxane yields5-butyryl-6-methyl-benzofuran-2-carboxylic acid, M.P. -157.

EXAMPLE 9' (a) Starting from 4.6 g. of4,6-dimethyl-5-butyrylbenzofuran-Z-carboxylic acid, 1.0 g. ofparaformaldehyde and 1.75 g. of dimethylamine hydrochloride, crude 4,6-dimethyl 5 (2-dimethylaminomethyl-butyryl)-benzo furan-Z-carboxylic acidhydrochloride is obtained analogously to Example 1(a). It is convertedwith 5.0 g. of sodium acetate and 50 ml. of glacial acetic acid into4,6- dimethyl-5-(Z-methylene-butyryl)-benzofuran 2 carboxylic acid whichmelts a-t 208210 (from ethanol).

(b) The starting compound, 4,6-dimethyl-5-butyrylbenzofuran-2-carboxylicacid, is produced analogously to Example 1(b) from 12.3 g. of4,6-dimethyl benzofuran-2- carboxylic acid (cf. F. M. Dean et al., J.Chem. Soc. 1953, 1250126l) and 10.0 g. of butyryl chloride with 25.0 g.of aluminium chloride. After recrystallisation from benzene/hexane, the4,6-dimethyl-S-butyrylbenzofuran-Z- carboxylic acid melts at 190'-192.

EXAMPLE 10 (a) Starting from 5.6 g. of 4-chloro-5-butyryl-benzo-[b]thiophene-Z-carboxylic acid With 1.2 g. of paraformaldehyde and 2.5g. of dimethylamine hydrochloride, crude 4-chloro 5(2-dimethylaminomethyl-bntyryl)- ibenzo[b]thiophene-Z-carboxylic acidhydrochloride is obtained analogously to Example 1(a). It is convertedwith 1.7 g. of sodium acetate and 17 ml. of glacial acetic acid into4-chloro 5 (Z-methyIene-butyryl)-benzo[b]thiophene-2-carboxylic acidwhich melts at 239-241 (from ethyl acetate/dioxane) The4-chloro-5-butyryl-benzo [b]thiophene-2-carboxylic acid used as startingmaterial is produced as follows:

(b) 22.5 g. of o-chlorobenzaldehyde are added dropwise within 10 minutesto a boiling mixture of 20.0 g. of rhodanine, 37.5 g. of anhydroussodium acetate and 100 ml. of glacial acetic acid. The reaction mixtureis then stirred for another 20 minutes at the same temperature whereuponit is poured into 3 litres of ice water. The crude5-(o-chlorobenzylidene)-rhodanine precipitates. The crystals arefiltered off under suction and washed with 500 ml. of water. The moistproduct is then added to a solution of 25.0 g. of sodium hydroxide in1.8 litres of water. The reaction mixture is dissolved while stirring,heated to 75 within 10 minutes and kept at this temperature for 10minutes. The solution is cooled to 10 and 65 ml. of concentratedhydrochloric acid are added. The crude o-chloroa-mercapto-cinnamic acidprecipitates. The crude product is filtered 01f under suction, washedwith water and dissolved in 700 ml. of ether. The ether solution isdried with anhydrous magnesium sulphate and evaporated in vacuo. Theresidue is added in portions to a solution of 60 g. of iodine in 200 ml.of nitrobenzene which has been heated to 180, the addition being madewithin 2 minutes. The reaction mixture is stirred for another 2 minutes,then poured onto 1 kg. of ice and the suspension obtained is extractedtwice 'With 500 ml. of chloroform each time. The chloroform extract isshaken twice with 100 ml. of 2 N sodium hydroxide solution each, theaqueous alkaline solution is decoloured with active charcoal andsaturated sodium sulphite solution, the suspension is filtered and thepH of the filtrate is adjusted with concentrated hydrochloric acid to2-3. The crude carboxylic acid precipitates. It is filtered oil undersuction, Washed with water and recrystallised from dioxane/acetic acidethyl ester, whereupon the pure 4-chlorobenzo[b]thiophene-Z-carboxylicacid obtained melts at 246247 C.

('c) 9.0 g. of the carboxylic acid obtained according to (b) areconverted analogously to Example 1(b) into 4- cholor-5-butyryl benzo[b]thiophene 2 carboxylic acid which melts at 217219 (from acetic acidethyl ester). The conversion is performed according to Friedel-Craftswith 8.0 g. of butyryl chloride in the presence of 25.0 g. of aluminiumchloride.

EXAMPLE 11 (a) Crude6-methyl-5-[(Z-dimethylaminomethyl)-propionyl]-benzofuran-2-carboxylicacid hydrochloride is obtained by the process described in Example 8(a)starting from 4.6 g. of 6-methyl-5-propionyl-benzofuran-Z-carboxylicacid, 0.7 g. of paraformaldehyde and 1.9 g. of dimethylaminehydrochloride. It is converted with 2.5 g. of sodium acetate in 25 ml.of glacial acetic acid into 6-methyl-5-(2-methylene-propionyl)-benzofuran-2-carboxylic acid, M.P. 185-186(recrystallised from acetic acid ethyl ester).

(b) The starting material, 5-propionyl-2methyl-benzofuran-Z-carboxylicacid is produced analogously to Example 8(b) from6-methyl-benzofuran-2-carboxylic acid (cf. K. von Auwers, Ann. Chem. 408(1915) 255) with propionyl chloride and aluminium chloride innitrobenzene. After recrystallisation from dioxane. it melts at 180-182.

EXAMPLE 12 (a) Crude6-methyl-5-[(Z-dimethylaminomethyl)-valeroyl]-benzofuran-2-carboxylicacid hydrochloride is obtained according to Example 8(a) starting from6-methyl- S- valeroyl-benzofuran-Z- carboxylic acid, paraformaldehydeand dimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into 1-methyl-5- (2-methylene-valeroy1) benzofuran 2carboxylic acid. M.P. 160-162 (recrystallised from benzene/ethylacetate).

(b) The starting material, 6-methyl-5-valeroy1-benzofuran-Z-carboxylicacid is produced analogously to Example 8(b) from6-methyl-benzofuran-Z-carboxylie acid (cf. K. von Auwers, Ann. Chem. 408(1915 255 with valeroyl chlorde and aluminium chloride in nitrobenzene.It melts at 154155 (recrystallised from acetic acid ethyl ester).

EXAMPLE 13 (a) Crude 6 methyl 5 [2 dimethylaminomethyl-3-methyl-butyryl]benzofuran-2 carboxylic acid dihydrochloride is obtainedanalogously to Example 1(a) starting from 6 methyl 5-(3-methyl-butyryl)-benzofuran-2-carboxylic acid with paraformaldehydeand dimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into6-methyl-5-(2-methylene-3-methylbutyryl)-benzofuran-2-carboxylic acid,M.P. 15 3154 (recrystallised from acetic acid ethyl ester).

(b) The starting compound,6-methyl-5-(3-methyl-butyryl)-benzofuran-2-carboxylic acid, is producedanalogously to Example 8(b) from 6-methyl-benzofuran-2-carboxylic acid(cf. K. von Auwers, Ann. Chem. 408 (1915) 255) with isovaleroyl chlorideand aiuminium chloride in nitrobenzene. It melts at 154156(recrystallised from ethyl acetate).

EXAMPLE 14 (a) Crude 6-methoxy 5 [(2-dimethylaminomethyl)-propionyl]-benzofuran-2-carboxylic acid hydrochloride is obtainedanalogously to Example 8(a) starting from 6-methoxy-S-propionyl-benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into 6- methoxy 5 2 -methylene propionyl)benzofuran-2- carboxylic acid, M.P. 165-167 (recrystallised frombenzene).

(b) The starting compound, 6-methoxy-5-propionylbenzofuran-Z-carboxylicacid, is produced analogous to Example 8(b) from6-methoxy-benzofuran-2-carboxylic acid (cf. W. Will and P. Beck, Ber.19, 1777 (1886)) with propionyl chloride and aluminium chloride innitrobenzene. It melts at 2l8220 (recrystallised from ethyl acetate).

EXAMPLE 15 (a) Crude6-methoxy-5-[(2-dimethylaminomethyD-butyryl]-benzofuran-2-carboxylicacid hydrochloride is obtained analogously to Example 8(a) starting from6-methoxy-5-butyryl benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into 6-methoxy- 5 (2 methylene butyryl) benzofuran 2carboxylic acid M.P. 153-154" (recrystallised from benzene).

'(b) The starting compound, 6 methoxy- 5 butyrylbenzofuran-Z-carboxylicacid is produced from 6-methoxy-benzofuran-Z-carboxylic acid (of. W.Will and P. Beck, Ber. 19, 1777 (1886)) with butyryl chloride andaluminium chloride in nitrobenzene. It melts at 189190 (recrystallisedfrom ethyl acetate).

EXAMPLE 16 (a) Starting from 6-ethoxy 5 butyryl benzofuran-2- carboxylicacid, paraformaldehyde and dimethylamine hydrochloride, crude 6 ethoxy 5[(2 dimethylaminemethyl)-butyryl] benzofuran 2 carboxylic acidhydrochloride is obtained analogously to Example 8(a). It is convertedwith sodium acetate in glacial acetic acid into 6-ethoxy-5-(2methylene-butyryl) benzofuran 2 carboxylic acid, M.P. 143-l44(recrystallised from ethanol/ water).

(b) The starting compound, 6-ethoxy-5-butyryl-benzofuran-Z-carboxylicacid, is produced analogously to Example 8(b) from6-ethoXy-benzofuran-Z-carboxylic acid (cf. W. Will and P. Beck, Ber. 19(1886) 1777) with butyric acid chloride and aluminium chloride innitrobenzene. The compound melts at 203-205 (recrystallised fromethanol).

EXAMPLE 17 (a) Crude 6-ethyl 5 [(2 dimethylaminornethyD-butyryl]-benzofuran-2-carboxylic acid hydrochloride is obtainedanalogously to Example 8(a) from 6-ethyl-5-butyryl-benzofuran-2-carboxylic acid, paraformaldehyde and dimethylaminehydrochloride. It is converted with sodium acetate in glacial aceticacid into 6-ethyl-5-(2 methylene-butyryl)-benzofuran 2 carboxylic acid,M.P. 121-122 (recrystallised from benzene).

(b) The starting compound, 6-ethyl-5-butyryl-benzofuran-Z-carboxylicacid is produced analogously to Example 8(b) from6-ethyl-benzofuran-Z-carboxylic acid with butyric acid chloride andaluminium chloride in nitrobenzene. 6-ethyl-S-butyryl-benzofuran-Zcarboxylic acid melts at 152-153 (recrystallised from acetic acid ethylester).

6-ethyl-benzofuran-2-carboxylic acid is also produced as follows:

(0) 50.0 g. of m-ethylphenol, 55.0 g. of malic acid and ml. ofcencentrated sulphuric acid are slowly heated to while stirring andstirring is continued at this temperature for 20 minutes. The reactionmixture is then poured onto 2 kg. of ice and extracted twice With 500ml. of ether each time. The combined ether extracts are washed with 200ml. of water and 200 ml. of concentrated aqueous sodium hydrogencarbonate solution,

dried over magnesium sulphate and concentrated. The residue, crude7-ethyl coumarin, is used as crude product.

((1) 30.4 g. of 7-ethy1 coumarin are dissolved in 40 ml. of chloroformand 29.0 g. of bromine in 20 ml. of chloroform are added dropwise whilestirring. The temperature of the reaction mixture is kept between 20 and25 by occasional cooling in an ice bath. The reaction mixture is thenstirred for another 20 minutes at room temperature and concentrated at50 under reduced pressure. The residue is added in portions to asolution of 80.0 g. of potassium hydroxide in 160 ml. of ethanol, whichsolution has been heated to 30, and the reaction temperature is kept at30-40 by cooling. The reaction mixture is then stirred for 30 minutes atroom temperature and for 30 minutes at 80, after which it is poured into1 litre of ice water. The aqueous, alkaline solution is washed twicewith 300 ml. of ether each time, acidified with concentratedhydrochloric acid to pH 23 and the precipitated crude product isfiltered ofl under suction. The crude product is recrystallised fromethanol and dried in vacuo at 80 whereupon the6-ethyl-benzofuran-Z-carboxylic acid obtained melts at 152-154".

EXAMPLE 18 (a) Crude 6-chloro [(2 dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic acid is obtained analo gously toExample 8(a) starting from 1.0 g. of 6-chloro-5-butyryl-benzofuran-Z-carboxylic acid, 0.16 g. of paraforrnaldehyde and0.385 g. of dimethylamine hydrochloride. It is converted with sodiumacetate in glacial acetic acid intoS-(Z-methyIene-butyryl)-6-chloro-benzofuran-Z-carboxylic acid.Recrystallised from benzene/ acetic acid ethyl ester, it melts at188-189".

The starting compound, 6-chloro-S-butyryl-benzofuran- 2-carboxylic acid,is produced as follows:

(b) 80 g. of 2-chloro-4-hydroxy-butyrophenone (cf. Belgian Pat. No.612,755) are slurried in 400 ml. of water, and 100 ml. of 4 N sodiumhydroxide solution are added. A clear solution is formed. 20 g. ofsodium borohydride are added an the whole is stirred for 5 hours at roomtemperature. The solution is then cooled with ice and hydrochloric acidis added dropwise until a pH of 3-4 has been attained. The suspension isstirred for another half hour, and then the crystals obtainedof 3-chloro-4-(1-hydroxybuty1)phenol are filtered off under suction. They areused immediately in the crude state.

(c) The moist crystal mass of 3-chloro-4-(1-hydroxybutyl)phenol is addedto a solution of 200 g. of sodium hydroxide in 500 ml. of water, thesolution formed is heated to 70 and 150 g. of chloroform are addeddropwise within 2 hours. During the addition, the temperature of thereaction mixture must be 70-80". The mixture is stirred for 20 minutesat 70 and then cooled to room temperature. The yellow crystal mass whichprecipitates, which consists of the sodium salt of3-ch1oro-4-(1-hydroxy-butyl)-2-formyl-phenol, is filtered off undersuction. The pH of the filtrate is adjusted to 23 with concentratedhydrochloric acid, the filtrate is extracted twice with 100 ml. of ethereach time and the combined ether extracts are washed with 100 ml. ofwater, after which they are stirred for hours with 200 ml. ofconcentrated sodium hydrogen sulphite solution. The crystals obtained,which consist of the bisulphite adduct of 3-chloro-4-(l-hydroxy-butyl)-6-formyl-phenol, are filtered off undersuction and washed first with 50 ml. of ether and then with 50 ml. ofwater. The crystals are then slurried in 100 ml. of water, 100 ml. ofether are poured in, ml. of concentrated hydrochloric acid are added andthe mixture is stirred for 2 hours whereupon the crystals dissolve. Theether phase is removed, washed with 50 ml. of water, dried overmagnesium sulphate and concentrated. The residue consists 6.5 g. of3-chloro-4-(1- hydroxy-butyl)-6-formyl phenol, which is used in thecrude state.

(d) 6.5 g. of crude 3 chloro-4-(1-hydroxy-butyl)-6- formyl phenol aredissolved in 30 ml. of methylethyl ketone, 4.0 g. of potassium carbonateare added and the mixture is refluxed while stirring. 8 g. ofbromomalonic acid diethyl ether are then added dropwise within 10minutes whereupon the reaction mixture is refluxed for 5 hours whilestirring. The solvent is then distilled off, the residue is taken up in50 ml. of water, concentrated hydrochloric acid is added until pH 3 isattained and the mixture is extracted twice with 100 ml. of ether eachtime. The ether solutions are washed with 100 ml. of water, dried overmagnesium sulphate and concentrated. A solution of 5 g. of potassiumhydroxide, 5 ml. of water and 50 ml. of ethanol is added to the residueand the mixture is refluxed for 2 hours. 200 ml. of water are then addedand the aqueous-alkaline solution is washed twice with 100 ml. of ethereach time. The aqueous solution is acidified with concentratedhydrochloric acid and extracted twice with 100 ml. of ether each time.The ether extracts are dried and concentrated. On standing, the residuecrystallises and is recrystallised from benzene. In this way, 1.8 g. of6-chloro-5-(l-hydroxy-butyl)-benzofuran-2-carboxylic acid, M.P.194-196", are obtained.

(e) 1.8 g. of 6-chloro-5-(1-hydroxy-butyl)-benzofuran- 2-carboxylic acidare dissolved in 20 ml. of acetone, the solution is cooled to 0 and asolution of 0.54 g. of CrO in 0.5 ml. of concentrated sulphuric acid and1.5 ml. of water is added. The reaction mixture is stirred for 30minutes, then distributed with 100 ml. of ether and 100 ml. of water,the ether layer is dried over magnesium sulphate and concentrated. Theresidue is recrystallised from benzene/ethyl acetate and yields 1.2 g.of 5-butyryl-6- chloro-benzofuran-2-carboxylic acid which melts at 214-215.

EXAMPLE 19 (a) Starting from 3.6 g. of4-chloro-5-butyryl-benzofuran-2-carboxylic acid, 0.48 g. ofparaformaldehyde and 1.15 g. of dimethylamine hydrochloride, crude4-chloro-5- [2 dimethylaminomethyl)-butyryl]-benzofuran 2-carboxylicacid hydrochloride is obtained analogously to Example 8(b). It isconverted with 2.0 g. of sodium acetate and 20 ml. of glacial aceticacid into 4-chloro-5-(2-methylene-butyryl)-benzofuran 2-carboxylic acid,M.P. 156- 158 (recrystallised from benzene/ethyl acetate).

The 4 chloro-5-butyryl-benzofuran-2-carboxylic acid used as startingmaterial is produced as follows:

(b) The crude sodium salt of 3-chloro-4-(1-hydroxybutyl)-2-formyl phenolobtained in Example 18(0) as side product is slurried in 200 ml. ofwater, the pH is adjusted to 3 with hydrochloric acid and the slurry isextracted twice with 100 ml. of ether each time. The ether extracts arewashed with 100 ml. of water, dried over magnesium sulphate andconcentrated. The residue, crude 3-chloro- 4-(l-hydroxy-butyl)-2-formylphenol (30 g.) is used in the crude state.

(c) 8.2 g. of 4-chloro-5-(1-hydroxy-butyl)benzofuran- Z-carboxylic acidare obtained analogously to Example 18(d) from 30 g. of 3chloro-4-(1-hydroxy-butyl)-2- formyl phenol with 20 g. of potassiumcarbonate and 30 g. of bromomalonic acid diethyl ester in 100 ml. ofmethylethyl ketone. Recrystallised from benzene/acetic acid ethyl ester,the compound melts at 173-175".

'(d) 4.5 g. of 4-chloro-5-butyryl-benzofuran-Z-carboxylic acid areobtained analogously to Example 18(e) from 7.6 g. of4-chloro-5-(l-hydroxy-butyl)-benzofuran-2-carboxylic acid in ml. ofacetone with a solution of 2.2 g. of chromium trioxide in 6 ml. of waterand 2 ml. of concentrated sulphuric acid. Recrystallised from benzene/ethyl acetate, the compound melts at 133-134".

EXAMPLE 20 (a) 7.2 g. of 3,6-dimethyl-5-butyryl-benzofuran-Z-carboxylicacid methyl ester and 3.3 g. of dimethylamine hydrochloride are meltedand the melt is stirred for 2 hours at 140. The melt obtained consistsof crude 3,6-dimethyl- (2dimethylaminomethyl-butyryl)-benzofuran-2-carboxylic acid methyl esterhydrochloride. This is refluxed for minutes with a solution of 80 ml. of1 N sodium hydroxide solution and 80 ml. of ethanol and, after dilutionwith 300 ml. of ice water, it is acidified to pH 3 with concentratedhydrochloric acid. The precipitate formed is filtered off under suctionand, after drying in vacuo, it is purified by chromatographing oversilica gel. The 3,6 dimethyl-S-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid, when recrystallised from benzene/heptane, melts at152-154".

The 3,6 l dimethyl 5 butylryl-benzofuran-2-carboxylic acid methyl esterused as starting material is produced as follows:

(b) 10.4 g. of 3,6-dimethyl-S-butyryl-benzofuran-2-carboxylic acid areadded in portions over a period of 30 minutes to a boiling slurry of 7g. of potassium carbonate in 80 ml. of acetone. Simultaneously asolution of 5 ml. of dimethyl sulphate in 30 ml. of acetone is added tothe reaction mixture from a dropping funnel. On completion of theaddition, the mixture is refluxed for another 3 hours while stirring,then cooled, the precipitate is filtered off under suction and is washedwith 50 ml. of acetone. The filtrate and washing liquor are combined andevaporated and the residue is recrystallised from carbontetrachloride/heptane. The 3,6-dimethyl-S-butyryl-benzofuran-2-carboxylic acid methyl ester formed melts at 101-105".

(c) The 3,6 dimethyl-S-butyryl-benzofurari-Z-carboxylic acid is obtainedanalogously to Example 8(b) from 3,6-dimethyl-benzofuran-2-carboxy1icacid (cf. Fries and Finkewirth, Chem. Ann. 362 (1908) 50) with butyricacid chloride and aluminium chloride in the nitrobenzene. The compoundmelts at 185-187 (recrystallised from benzene/ ethyl acetate).

EXAMPLE 21 (a) 0.5 g. of 6methyl-5-[2-(methylthiomethyl)-butyryl]-benzofuran-2-carboxylic acid aredissolved in 5 ml. of acetone, 0.5 g. of dimethyl sulphate are added andthe solution is left to stand for 3 days at room temperature. Thesolvent is then evaporated under reduced pressure and the residueconsisting of crude6-methyl-5-[2-(dimethyl-thioniummethyl)-butyryl]-benzofuran 2 carboxylicacid methyl sulphate, is dissolved in 5 ml. of water. 2.5 ml. ofsaturated sodium hydrogen carbonate solution are added to the solutionformed and the reaction mixture is heated for 1 hour in a steam bath.The cooled solution is then acidified to pH 2-3 with hydrochloric acid,stirred for half an hour at room temperature and the precipitatedcrystals are filtered off under suction, dried and recrystallised frombenzene. 0.3 g. of 6-methyl-5-[2-(methylene)- butyryl]-benzofuran-2carboxylic acid, M.P. 141142, are obtained.

The 6 methyl 5 [2-(methyl-thiomethyl)-butyryl]- benzofuran-2-carboxylicacid used as starting material is produced as follows:

(b) 6.8 g. of 6-methyl-5-[2-dimethylaminomethyl)- butyryl]-benzofuran 2carboxylic acid hydrochloride (M.P. 187-188") are dissolved in 200 ml.of water, 4.04 g. of sodium hydrogen carbonate are added in portions tothe solution and a constant stream of methyl mercaptan is bubbledthrough the mixture. While continuing the introduction of methylmercaptan, the mixture is heated to 90 and is kept for 2 hours at thistemperature whereupon the stream of gas is cut off and the solution iscooled. The pH of the solution is adjusted to 2-3 with concentratedhydrochloric acid and the precipitate formed is filtered oif undersuction, dried in vacuo and recrystallised from a small amount of aceticacid ethyl ester. In this way, 5.2 g. of6-methyl-5-[Z-(methylthiomethyl)-butyryl]- benzofuran-Z-carboxylic acid,M.P. 151-152, are obtained.

- 16 EXAMPLE 22 (a) 10 ml. of water and 5 ml. of a saturated sodiumhydrogen carbonate solution are added to 6-methyl-5-[2-(methylsulphonylmethyl) butyryl]-benzofuran 2 carboxylic acid and thenthe solution is refluxed for 1 /2 hours. It is allowed'to cool and thesolution is acidified to pH 2-3 with concentrated hydrochloric acid. Themixture is stirred for another 30 minutes and then the precipitatedcrystals are filtered off under suction, dried in vacuo andrecrystallised from benzene. In this way, 0.5 g. of6-methyl-5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid, M.P.141-142 are obtained.

The 6-methyl-5- [2- (methyl-sulphonylmethyl) butyryl]benzofuran-Z-carboxylic acid used as starting material is produced asfollows:

(b) 3.1 g. of6-dimethyl-5-[Z-(methylthiomethyD-butyryl]-benzofuran-2-carboxylic acid(production see Example 21) are slurried in 15 ml. of glacial aceticacid and 3.6 g. of 40% peracetic acid are so added dropwise to themixture while cooling with ice that the reaction temperature remainsbetween 15 and 20. The reaction mixture is then stirred for 15 hours atroom temperature'and the precipitated crystal mass is filtered off undersuction. Recrystallised from ethyl acetate/dioxane, 2.8 g. of 6-methyl-S-[Z-(methylsulphonylmethyl) butyryl] benzofuran-2-carboxylicacid, M.P. 201-203 are obtained.

EXAMPLE 23 (a) A solution of 6-methyl-5-(Z-methyIene-butyryl)-benzofuran-Z-carboxylic acid methyl ester in 5 ml. of ethanol is heatedto reflux temperature, 2 ml. of 1 N sodium hydroxide solution are addedand the mixture is refluxed for another minute whereupon it is dilutedwith 70 ml. of ice water. The solution is then washed with 50 ml. ofether, the pH of the aqueous-alkaline phase is adjusted to 2-3 withhydrochloric acid and the mixture is stirred for 30 minutes. Theprecipitate formed is filtered olf under suction, dried in vacuo andrecrystallised from benzene. In this way, 0.4 g. of6-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid, M.P. 141-142", are obtained.

The 6 methyl-5-(Z-methylene-butyryl)-benzofuran-2- carboxylic acidmethyl ester used as starting material can be produced as follows:

(b) 5.0 g. of anhydrous potassium carbonate are slurried in 20 ml. ofacetone and the slurry is brought to reflux temperature. A solution of7.5 of 6-methyl-5-butyryl-benzofuran-Z-carboxylic acid and 3.75 ml. ofdimethyl sulphate in 70 ml. of acetone is added dropwise to thissuspension within 15 minutes whereupon the reaction mixture is refluxfor another hour and cooled. Insoluble salts are then filtered off, theacetone solution is concentrated and the residue is recrystallised frommethanol. 7.3 g. of 6 methyl-5-butyryl-benZofuran-2-carboxylic acidmethyl ester, M.P. 91-92, are obtained in this way.

(c) 5.5 g. of the 6-methyl-5-butyryl-benzofuran-Z-carboxylic acid methylester produced in (b) above are refluxed for 24 hours with 1.2 g. ofparaformaldehyde and 3.2 g. of dimethylamine hydrochloride in 12ml. ofmethanol. The methanol is then evaporated, 30 ml, of acetic acid ethylester are added to the residue which is then left to stand for 2 days ina refrigerator. The'crystal mass so obtained is then filtered off andrecrystallised from acetonitrile whereupon 2.4 g. of6-methyl-5-[2-(dimethylaminoethyl)-butyryl]-benzofuran-2-carboxylic acidmeth yl ester hydrochloride, M.P. 176-178, are obtained.

(d) 1.2 g. of the6-methyl-5-[Z-(dimethylaminomethyl)-butyryl]-benzofuran-2-carboxyliccaid methyl ester hydrochloride are refluxed for 2 hours with 1.2 g. ofsodium acetate and 20 ml. of glacial acetic acid. The glacial aceticacid is then evaporated in a rotary evaporator and the residue isdistributed between ml. of water and 100 ml. of ether. After washing theether phase with 100 ml. of water, it is removed, dried with 100 ml. ofsatu- 17 rated sodium hydrogen carbonate solution over magnesiumsulphate and concentrated. The residue is recrystallised from methanoland yields 0.6 g, of 6-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid methyl ester, M.P. 8586.

EXAMPLE 24 (a) 1.2 g. of 6methyl-5-(2-bromo-2-methyl-propionyl)-benzofuran-2-carboxylic acid in 80ml. of benzene are stirred with 1.8 g. of mercury acetate for 4 hoursunder reflux. The reaction mixture is then poured into a mixture of 100g. of ice and ml. of concentrated hydrochloric acid, well stirred andthe precipitate formed, consisting of mercury bromide and mercurychloride, is filtered off. The residue is washed with 100 ml. of aceticacid ethyl ester. The filtrate is then put into a separating funnel, theorganic phase is removed, washed with 50 ml. of water, dried overmagnesium sulphate and concentrated. The residue is recrystallised frombenzene and 6- methyl-S-(Z-methylene-propionyl) benzofuran 2 carboxylicacid, M.P. 185186.

The starting material,6-methyl-5-(2-bromo-2-methylpropionyl)-benzofuran-2-carboxylic acid, isproduced as follows:

(b) 3.0 g. of 6-methyl-5-isobutyryl-benzofuran-Z-carboxylic acid aredissolved in 30 ml, of glacial acetic acid and 0.7 ml. of bromine areadded dropwise within minutes to this solution at 50. The whole isstirred for another 15 minutes at the same temperature, after which theglacial acetic acid is evaporated in a rotary evaporator and the residueis recrystallised from ethyl acetate/dioxane. 3.65 g. of6-methyl-5-(2-bromo-2-methylpropionyl)-benzofuran-2-carboxylic acid,M.P. 231-233", are obtained in this way.

(0) The 6-methyl-5-isobutyryl-benzofuran-2-carboxylic acid is producedanalogously to Example 8(b) from 6-methyl-benzofuran-2-canboxylic acid(cf. K. von Auwers, Ann. Chem. 408, (1915) 255) with isobutyryl chlorideand aluminium chloride in nitrobenzene. It melts at 174-175(recrystallised from methylethyl ketone).

The following examples illustrate the production of tablets and drages:

EXAMPLE 2.5

1000 g. of 4-chloro-5- (Z-methylene-butyryl)-indole-2- carboxylic acidare mixed with 550 g. of lactose and 292 g. of potato starch, themixture is moistened with an aqueous solution of 8 g. of gelatine andgranulated through a sieve. After drying, 60 g. of potato starch, 60 g.of talcum, 10 g. of magnesium stearate and g. of colloidal silicondioxide are mixed in and the mixture is pressed into 10,000 tablets eachweighing 200 mg. and containing 100 mg. of active substance. If desired,the tablets can be grooved for better adaptation of the dosage.

EXAMPLE 26 A granulate is produced from 1000 g. of5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid, 379 g. of 1actoseand the aqueous solution of 6 g. of gelatine. After drying, thegranulate is mixed with 10 g. of colloidal silicon dioxide, 40 g. oftalcum, 60 g. of potato starch and 5 g. of magnesium stearate and themixture is pressed into 10,000 drage cores. These are then coated with aconcentrated syrup consisting of 533.5 g. of crystallised saccharose, 20g. of shellac, g. of gum arabic, 2.50 g. of talcum, 20 g. of colloidalsilicone dioxide and 1.5 g. of dyestulf, and dried. The drages obtainedeach weight 240 mg. and contain mg. of active substance.

What we claim is:

1. A compound of the Formula I COOH wherein R is hydrogen or loweralkyl;

Y is hydrogen, methyl, fiuoro, chloro or bromo; and each of Z and Ztaken individually is hydrogen, lower alkyl, lower alkoxy, fluoro,chloro or bromo; and

the pharmaceutically acceptable salts thereof with a base. 2. A compoundaccording to claim 1 which compound is6-methyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid.

3. A compound according to claim 1 which compound is6-methyl-5-(Z-methylene-propionyl)-benzofuran-2-carboxylic acid.

4. A compound according to claim 1 which compound is6-methyl-5-(Z-methylene-valeryl)-benzofuran-2-carboxylic acid.

5. A compound according to claim 1 which compound is6-methyl-5-(2-methylene-3-methyl-butyryl)-benzofuran- Z-carboxylic acid.

6. A compound according to claim 1 which compound is3,6-dimethyl-5-(2-rnethylene-butyryl)-benzofuran-2-carboxylic acid.

7. A compound according to claim 1 which compound is 6ethyl-5-(Z-methyIene-butyryl)-benzofuran-2-carboxylic acid.

8. A compound according to claim 1 which compound is 6methoxy-S-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid.

9. A compound according to claim 1 which compound is4-chloro-5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid.

10. A compound according to claim 1 which compound is 6-chloro-5-(Z-methylene-butyryl) -benzofuran-2-carboxylic acid.

References Cited ALEX MAZEL, Primary Examiner B. I. DENTZ, AssistantExaminer US. Cl. X.R.

